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Gut commensal Limosilactobacillus reuteri induces atypical memory-like phenotype in human dendritic cells in vitro
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-2321-9369
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-5012-4779
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0001-8525-9895
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 82022 (English)In: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 14, no 1, article id 2045046Article in journal (Refereed) Published
Abstract [en]

Memory-like responses in innate immune cells confer nonspecific protection against secondary exposures. A number of microbial agents have been found to induce enhanced or diminished recall responses in innate cells, however, studies investigating the ability of probiotic bacteria to trigger such effects are lacking. Here, we show that priming of human monocytes with a secretome from the gut probiotic bacterium Limosilactobacillus (L.) reuteri induces a mixed secondary response phenotype in monocyte-derived dendritic cells (mo-DCs), with a strong IL-6 and IL-1β response but low TNFα, IL-23 and IL-27 secretion. Instead, blood DC priming with L. reuteri-secretome resembles a tolerant state upon secondary exposure. A similar pattern was found in conventional and gut-like (retinoic acid exposed) DCs, although retinoic acid hampered TNFα and IL-6 production and enrichment of histone modifications in L. reuteri-secretome primed mo-DC cultures. Further, we show that the memory-like phenotype of mo-DCs, induced by priming stimuli, is important for subsequent T helper (Th) cell differentiation pathways and might determine the inflammatory nature of Th cells. We also show enhanced recall responses characterized by robust inflammatory cytokines and lactate production in the gut-like mo-DCs derived from β-glucan primed monocytes. Such responses were accompanied with enriched histone modifications at the promoter of genes associated with a trained phenotype in myeloid cells. Altogether, we demonstrate that a gut commensal-derived secretome prompts recall responses in human DCs which differ from that induced by classical training agents such as β-glucan. Our results could be beneficial for future therapeutic interventions where T cell responses are needed to be modulated.

Place, publisher, year, edition, pages
2022. Vol. 14, no 1, article id 2045046
Keywords [en]
Limosilactobacillus reuteri, dendritic cells, T helper cells, innate immune memory, epigenetics
National Category
Biological Sciences Immunology in the medical area
Identifiers
URN: urn:nbn:se:su:diva-203478DOI: 10.1080/19490976.2022.2045046ISI: 000765991300001PubMedID: 35258405Scopus ID: 2-s2.0-85125981330OAI: oai:DiVA.org:su-203478DiVA, id: diva2:1649945
Available from: 2022-04-05 Created: 2022-04-05 Last updated: 2022-05-09Bibliographically approved
In thesis
1. Functions and memory features of adaptive- and innate immune cells in physiological and inflammatory settings
Open this publication in new window or tab >>Functions and memory features of adaptive- and innate immune cells in physiological and inflammatory settings
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The immune system is a complex but well-regulated network which cooperates with the microbiota to maintain optimal homeostasis under physiological settings. A number of factors display the capacity to alter the immune system and thus microbiota crosstalk including host genetics, diet, environmental influences and drugs such as antibiotics or chemotherapeutic agents.

We and others have previously demonstrated immune regulatory capacities of the gut commensal Limosilactobacillus reuteri (L. reuteri) that seem to act via myeloid cells. In paper I, we have further shown that priming of blood dendritic cells (DCs) or monocytes with L. reuteri-derived cell free supernatant (CFS) modifies how these cells respond to future stimulus challenge, even after monocytes differentiation to DCs (mo-DCs). Notably, priming conditions in mo-DCs skewed subsequent T-helper cell responses. In paper II, we continued to elaborate on whether microbial and gut-associated metabolites modify chemotherapy-induced effects. Thus far, we could show that the CFS from probiotic bacteria might imprint immune cells to modulate inflammatory responses when intestinal epithelial cells are compromised by chemotherapy exposure. In paper III, we investigated how chemotherapy agent Doxorubicin (Doxo) affects bone marrow resident mesenchymal stromal cells (BM MSCs) which support antibody secreting cells (ASCs) responsible for serological memory. Our findings have shown that Doxo-induced alterations in BM MSCs are not sufficient to disrupt their support to ASCs, thus alternative or additional factors might be implicated in ASC preservation during chemotherapy. Lastly, in paper IV, we investigated how Doxo affects secondary lymphoid organs and we found that splenic compartment is more prominently affected by Doxo treatment compared to its lymph node counterpart in an animal model of rhesus macaques.

Collectively, this thesis outlines novel perceptions on innate immune memory-like capacity and how gut-associated factors influence such recall responses in innate immune cells. Further, this thesis increases our knowledge on how adaptive immune cells, required for long-term serological memory, are preserved during toxic conditions such as those induced by chemotherapy treatment.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2022. p. 77
Keywords
Innate immune memory, Limosilactobacillus reuteri, dendritic cells, lymphocytes, cytokines, immunological memory, intestinal epithelial cells, chemotherapy, bone marrow, secondary lymphoid organs
National Category
Immunology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-204457 (URN)978-91-7911-840-2 (ISBN)978-91-7911-841-9 (ISBN)
Public defence
2022-08-26, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:00 (English)
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Available from: 2022-06-01 Created: 2022-05-09 Last updated: 2022-05-19Bibliographically approved

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Lasaviciute, GintareBarz, Myriamvan Der Heiden, MariekeArasa, ClaudiaTariq, KanwalÖstlund Farrants, Ann-KristinSverremark-Ekström, Eva

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Lasaviciute, GintareBarz, Myriamvan Der Heiden, MariekeArasa, ClaudiaTariq, KanwalÖstlund Farrants, Ann-KristinSverremark-Ekström, Eva
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